Viral respiratory tract infections are the most common cause of acute morbidity in individuals of all ages worldwide. Picornaviruses alone are responsible for ~80% of all acute respiratory infections during peak season and are a major cause for restricted activity and physician consultation. Despite the generally benign course of the common cold caused by picornaviruses, it is the main culprit for acute exacerbation of serious respiratory system disorders, for example bronchial asthma or chronic obstructive pulmonary disease. The mechanisms of primary picornaviral respiratory tract infection or secondary exacerbation of pulmonary disease are not fully understood. Moreover, no specific anti-viral chemotherapy is available. A major impediment to advances in research of pathogenic mechanisms and anti-viral drug development is the absence of a practical animal model for the common cold. Generally, studies of pathogenesis and pharmacologic testing rely on deliberate infection of volunteers. We generated mice transgenic for the human intercellular adhesion molecule-1 (hICAM-1) gene, which exhibit hICAM-1 expression in respiratory epithelium similar to humans. These mice in principle are susceptible to infection with the vast majority of picornaviruses, which recognize hICAM-1 as a cellular receptor. This project aims to establish a murine model for the common cold by generating picornaviruses with respiratory tropism capable of propagating and eliciting characteristic lesions and host responses in the respiratory tract of hICAM-1 transgenic mice. Our research intends to generate a practical small animal model for the common cold, a major cause for pulmonary illness and associated health care expenditure worldwide. This disease model would provide far improved opportunities to unravel mechanisms of viral respiratory tract infection and to test new therapeutic approaches benefiting patients at risk from exacerbation of underlying pulmonary disease.